The effect of amycretin, a unimolecular glucagon-like peptide-1 and amylin receptor agonist, on body weight and metabolic dysfunction in mice and rats.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2025-07-23 DOI:10.1016/j.ebiom.2025.105862

Rune Ehrenreich Kuhre, Borja Ballarín-González, Christian Lehn Brand, Tine Glendorf, Kim Grimstrup Madsen, Karina Rahr Hjøllund, Wouter Frederik Johan Hogendorf, David Højland Ipsen, Sofia Lundh, Thomas Kruse, Signe Beck Petersen, Anna Secher, Andreas Vegge, Kirsten Raun

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引用次数: 0

Abstract

Background: Amycretin is a novel unimolecular glucagon-like peptide-1 (GLP-1) and amylin receptor agonist. This study aimed to determine its role in mitigating diet-induced metabolic disorders, such as obesity, insulin resistance, and fatty liver disease, in mice and rats.

Methods: Preclinical studies were conducted to characterise amycretin activation of GLP-1, amylin and calcitonin receptors, and determine the effects of amycretin administration on the metabolic health of mice and rats. Investigations included measurements of body weight and body composition, energy intake and energy expenditure, insulin sensitivity, metabolic dysfunction-associated steatotic liver disease (MASLD), and access in the mouse brain.

Findings: Amycretin activated human, mouse and rat GLP-1, amylin and calcitonin receptors in cell-based systems. In diet-induced obese (DIO) rats, amycretin administration for 21 days reduced total energy intake by 47% (95% CI (mean), kcal: vehicle: 2132-2493 vs. amycretin: 1044-1390) and lowered body weight by 18% (95% CI (mean), % change relative to pre-treatment: vehicle: 6.56-8.47 vs. amycretin: -10.48 to -12.74, p < 0.0001), while maintaining energy expenditure. Amycretin targeted key areas of the mouse brain that regulate food intake. Insulin sensitivity improved significantly with amycretin administration in DIO rats compared with vehicle controls, shown by higher glucose infusion rates during a hyperinsulinaemic euglycemic clamp. Additionally, amycretin improved histological hallmarks of MASLD, primarily by reducing steatosis.

Interpretation: Amycretin had various beneficial effects on metabolic health in mice and rats; effectively reducing body weight, enhancing insulin sensitivity, and improving MASLD activity scores. Thus, amycretin could be a promising therapeutic option for metabolic diseases including obesity and type 2 diabetes, warranting further clinical trials assessing its efficacy in humans.

Funding: Novo Nordisk A/S.

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amycretin是一种单分子胰高血糖素样肽-1和胰高血糖素受体激动剂，对小鼠和大鼠体重和代谢功能障碍的影响。

背景：Amycretin是一种新型的单分子胰高血糖素样肽-1 （GLP-1）和胰淀素受体激动剂。本研究旨在确定其在减轻小鼠和大鼠饮食引起的代谢紊乱（如肥胖、胰岛素抵抗和脂肪肝疾病）中的作用。方法：通过临床前研究，表征了amycretin对GLP-1、amylin和降钙素受体的激活，并确定了amycretin给药对小鼠和大鼠代谢健康的影响。调查包括测量体重和身体组成、能量摄入和能量消耗、胰岛素敏感性、代谢功能障碍相关的脂肪变性肝病（MASLD）和小鼠大脑中的通路。结果：Amycretin激活了人、小鼠和大鼠细胞系统中的GLP-1、amylin和降钙素受体。在饮食诱导的肥胖（DIO）大鼠中，给药21天使总能量摄入减少47% (95% CI（平均），大卡：对照：2132-2493 vs. amycretin: 1044-1390)，体重降低18% (95% CI（平均），相对于治疗前的变化百分比：对照：6.56-8.47 vs. amycretin: -10.48至-12.74,p < 0.0001)，同时保持能量消耗。Amycretin针对的是老鼠大脑中控制食物摄入的关键区域。与对照组相比，给药后胰岛素敏感性显著改善，表现为高胰岛素血症的正糖钳夹期间葡萄糖输注速率升高。此外，amycretin改善了MASLD的组织学特征，主要是通过减少脂肪变性。解释：Amycretin对小鼠和大鼠的代谢健康有多种有益作用；有效降低体重，提高胰岛素敏感性，改善MASLD活动评分。因此，amycretin可能是代谢性疾病（包括肥胖和2型糖尿病）的一种有希望的治疗选择，需要进一步的临床试验来评估其在人体中的疗效。融资：诺和诺德A/S。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.